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RISEDRONATE SODIUM 35MG ONCE A WEEK FILM-COATED TABLETS

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Risedronate sodium 35mg Once a Week film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 35 mg risedronate sodium, equivalent to 32.5 mg
risedronic acid.
Excipient with known effect:
Each film-coated tablet contains 109.7 mg of lactose monohydrate
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
Round light-orange film-coated tablet with “R16” engraved on one side and
plain on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral
fractures.
Treatment of established postmenopausal osteoporosis, to reduce the risk of
hip fractures (see section 5.1).
Treatment of osteoporosis in men at high risk of fractures (see section 5.1).

4.2

Posology and method of administration
The recommended dose in adults is one 35 mg tablet orally once a week. The tablet
should be taken on the same day each week.
The absorption of risedronate sodium is affected by food, thus to ensure adequate
absorption patients should take Risedronate Sodium 35 mg Once a Week film-coated
tablets:
Before breakfast: At least 30 minutes before the first food, other medicinal product or
drink (other than water) of the day.
Patients should be instructed that if a dose is missed, one Risedronate Sodium 35 mg
Once a Week film-coated tablets should be taken on the day that the tablet is
remembered. Patients should then return to taking one tablet once a week on the day
the tablet is normally taken. Two tablets should not be taken on the same day.

The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the
tablet to the stomach, the tablet should be taken while in an upright position with a
glass of plain water (≥120 ml). Patients should not lie down for 30 minutes after
taking the tablet (see section 4.4).
Supplemental calcium and vitamin D should be considered in cases where dietary
intake is inadequate.
Elderly patients: No dosage adjustment is necessary since bioavailability, distribution
and elimination is similar in the elderly (>60 years of age) compared to younger
subjects. This has also been shown in the very elderly 75 years old and above
postmenopausal population.
Patients with renal impairment: No dosage adjustment is required for those patients
with mild to moderate renal impairment. The use of risedronate sodium is
contraindicated in patients with severe renal impairment (creatinine clearance lower
than 30ml/min) (see sections 4.3 and 5.2).
Paediatric population: Risedronate is not recommended for use in children below age
18 due to insufficient data on safety and efficacy (also see section 5.1).
The optimal duration of bisphosphonate treatment for osteoporosis has not been
established. The need for continued treatment should be re-evaluated periodically
based on the benefits and potential risks of Risedronate Sodium 35 mg Once a Week
film-coated tablets on an individual patient basis, particularly after 5 or more years of
use.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
Hypocalcaemia (see section 4.4).
Pregnancy and lactation.
Severe renal impairment (creatinine clearance <30ml/min).

4.4

Special warnings and precautions for use
Foods, drinks (other than plain water) and medicinal products containing polyvalent
cations (such as calcium, magnesium, iron and aluminium) interfere with the
absorption of bisphosphonates and should not be taken at the same time as
Risedronate Sodium 35 mg Once a Week film-coated tablets (see section 4.5). In
order to achieve the intended efficacy, strict adherence to dosing recommendations is
necessary (see section 4.2).
Efficacy of bisphosphonates in the treatment of osteoporosis is related to the presence
of low bone mineral density and/or prevalent fracture.
High age or clinical risk factors for fracture alone are not sufficient reasons to initiate
treatment of osteoporosis with a bisphosphonate.

The evidence to support efficacy of bisphosphonates including risedronate in the very
elderly (>80 years) is limited (see section 5.1).
Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal
ulcerations and gastroduodenal ulcerations. Thus, caution should be used:
- In patients who have a history of oesophageal disorders which delay oesophageal
transit or emptying e.g. stricture or achalasia
- In patients who are unable to stay in the upright position for at least 30 minutes after
taking the tablet.
- If risedronate is given to patients with active or recent oesophageal or upper
gastrointestinal problems (including known Barrett's oesophagus).
Prescribers should emphasise to patients the importance of paying attention to the
dosing instructions and be alert to any signs and symptoms of possible oesophageal
reaction. The patients should be instructed to seek timely medical attention if they
develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing,
retrosternal pain or new/worsened heartburn.
Hypocalcaemia should be treated before starting Risedronate Sodium 35 mg Once a
Week film-coated tablets therapy. Other disturbances of bone and mineral
metabolism (i.e. parathyroid dysfunction, hypovitaminosis D) should be treated at the
time of starting Risedronate Sodium 35 mg Once a Week film-coated tablets therapy.
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local
infection (including osteomyelitis) has been reported in patients with cancer receiving
treatment regimens including primarily intravenously administered bisphophonates.
Many of these patients were also receiving chemotherapy and corticosteroids.
Osteonecrosis of the jaw has also been reported in patients with osteoporosis
receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered
prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g.
cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if
possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate
therapy, dental surgery may exacerbate the condition. For patients requiring dental
procedures, there are no data available to suggest whether discontinuation of
bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
Clinical judgment of the treating physician should guide the management plan of each
patient based on individual benefit /risk assessment.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with
bisphosphonate therapy, primarily in patients receiving long-term treatment for
osteoporosis. These transverse or short oblique, fractures can occur anywhere along
the femur from just below the lesser trochanter to just above the supracondylar flare.
These fractures occur after minimal or no trauma and some patients experience thigh
or groin pain, often associated with imaging features of stress fractures, weeks to
months before presenting with a completed femoral fracture. Fractures are often
bilateral; therefore the contralateral femur should be examined in bisphosphonatetreated patients who have sustained a femoral shaft fracture. Poor healing of these

fractures has also been reported. Discontinuation of bisphosphonate therapy in
patients suspected to have an atypical femur fracture should be considered pending
evaluation of the patient, based on an individual benefit risk assessment.
During bisphosphonate treatment patients should be advised to report any thigh, hip
or groin pain and any patient presenting with such symptoms should be evaluated for
an incomplete femur fracture.
This medicine contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should
not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
No formal interaction studies have been performed with risedronate sodium.
However, no clinically relevant interactions with other medicinal products
were found during clinical trials. In the Phase III osteoporosis studies with
daily dosing of risedronate sodium, acetyl salicylic acid or non-steroidal antiinflammatory drugs (NSAIDs) use was reported by 33% and 45% of patients
respectively. In the Phase III once a week study in postmenopausal women,
acetyl salicylic acid or NSAID use was reported by 57% and 40% of patients
respectively. Among regular acetyl salicylic acid or NSAIDs users (3 or more
days per week) the incidence of upper gastrointestinal adverse events in
patients treated with risedronate sodium was similar to that in control patients.
If considered appropriate risedronate sodium may be used concomitantly with
oestrogen supplementation (for women only).
Concomitant ingestion of medications containing polyvalent cations (e.g.
calcium, magnesium, iron and aluminium) will interfere with the absorption of
[Product name/to be completed nationally] (see section 4.4).
Risedronate sodium is not systemically metabolised, does not induce
cytochrome P450 enzymes, and has low protein binding.

4.6

Fertility, pregnancy and lactation
There are no adequate data from the use of risedronate sodium in pregnant
women. Studies in animals have shown reproductive toxicity (see section 5.3).
The potential risk for humans is unknown. Studies in animal indicate that a
small amount of risedronate sodium pass into breast milk. Risedronate sodium
must not be used during pregnancy or by breast-feeding women.

4.7

Effects on ability to drive and use machines
No effects on ability to drive and use machines have been observed.

4.8

Undesirable effects

Risedronate sodium has been studied in phase III clinical trials involving more than
15,000 patients. The majority of undesirable effects observed in clinical trials were
mild to moderate in severity and in most cases did not require cessation of therapy.


Adverse experiences reported in phase III clinical trials in postmenopausal
women with osteoporosis treated for up to 36 months with risedronate
sodium 5 mg/day (n=5020) or placebo (n=5048) and considered possibly or
probably related to risedronate sodium are listed below using the following
convention (incidences versus placebo are shown in brackets): very common
( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to <1/100); rare
( 1/10,000 to <1/1,000); very rare (<1/10,000).

Nervous system disorders:
Common: headache (1.8% vs. 1.4%)
Eye disorders:
Uncommon: iritis*
Gastrointestinal disorders:
Common: constipation (5.0% vs. 4.8%), dyspepsia (4.5% vs. 4.1%), nausea (4.3% vs.
4.0%), abdominal pain (3.5% vs. 3.3%), diarrhoea (3.0% vs. 2.7%)
Uncommon: gastritis (0.9% vs. 0.7%), oesophagitis (0.9% vs. 0.9%), dysphagia
(0.4% vs. 0.2%), duodenitis (0.2% vs. 0.1%), oesophageal ulcer (0.2% vs. 0.2%)
Rare: glossitis (<0.1% vs. 0.1%), oesophageal stricture (<0.1% vs. 0.0%),
Musculoskeletal and connective tissues disorders:
Common: musculoskeletal pain (2.1% vs. 1.9%)
Investigations:
Rare: abnormal liver function tests*
* No relevant incidences from Phase III osteoporosis studies; frequency based on
adverse event/laboratory/rechallenge findings in earlier clinical trials.
In a one-year, double-blind, multicentre study comparing risedronate sodium 5 mg
daily (n= 480) and risedronate sodium 35 mg weekly (n=485) in postmenopausal
women with osteoporosis, the overall safety and tolerability profiles were similar.
The following additional adverse experiences considered possibly or probably drug
related by investigators have been reported (incidence greater in the risedronate
sodium 35 mg than in the risedronate sodium 5 mg group): gastrointestinal disorders
(1.6% vs. 1.0%) and pain (1.2% vs. 0.8%).
In a 2 year study in men with osteoporosis, the overall safety and tolerability were
similar between the treatment and the placebo groups. Adverse experiences were
consistent with those previously observed in women.
Laboratory findings: Early, transient, asymptomatic and mild decreases in serum
calcium and phosphate levels have been observed in some patients.
The following additional adverse reactions have been reported during post-marketing
use (frequency unknown):
Eye disorders:
Iritis, uveitis

Musculoskeletal and connective tissues disorders:
Osteonecrosis of the jaw
Skin and subcutaneous tissue disorders:
Hypersensitivity and skin reactions, including angioedema, generalised rash, urticaria
and bullous skin reactions, some severe including isolated reports of Stevens Johnson
syndrome, toxic epidermal necrolysis and leukocytoclastic vasculitis.
Hair loss
Immune system disorders:
Anaphylactic reaction
Hepatobiliary disorders:
Serious hepatic disorders. In most of the reported cases the patients were also treated
with other products known to cause hepatic disorders.
During post-marketing experience the following reactions have been reported
(frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures
(bisphosphonate class adverse reaction)

4.9

Overdose
No specific information is available on the treatment of overdose with
risedronate sodium.
Decreases in serum calcium following substantial overdose may be expected.
Signs and symptoms of hypocalcaemia may also occur in some of these
patients.
Milk or antacids containing magnesium, calcium or aluminium should be
given to bind risedronate sodium and reduce its absorption. In cases of
substantial overdose, gastric lavage may be considered to remove unabsorbed
risedronate sodium.
The earliest symptom of hypocalcaemia is pins and needles’ sensation over the
extremities of hands and feet. Other symptoms include muscle or abdominal
cramps.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: 9.6.2 – Bisphosphonates, Medicines that act on bone and
on calcium metabolism.
ATC Code: M05BA07.
Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite
and inhibits osteoclast mediated bone resorption. The bone turnover is reduced while
the osteoblast activity and bone mineralisation is preserved. In preclinical studies
risedronate sodium demonstrated potent anti-osteoclast and antiresorptive activity,
and dose dependently increased bone mass and biomechanical skeletal strength. The
activity of risedronate was confirmed by measuring biochemical markers for bone

turnover during pharmacodynamic and clinical studies. In studies of postmenopausal
osteoporosis women, decreases in biochemical markers of bone turnover were
observed within 1 month and reached a maximum in 3-6 months. Decreases in
biochemical markers of bone turnover were similar with risedronate 35 mg once a
week and risedronate 5 mg daily at 12 months.
In a study in men with osteoporosis, decreases in biochemical markers of bone
turnover were observed at the earliest time point of 3 months and continued to be
observed at 24 months.
Treatment of Postmenopausal Osteoporosis:
A number of risk factors are associated with postmenopausal osteoporosis including
low bone mass, low bone mineral density, early menopause, history of smoking and a
family history of osteoporosis. The clinical consequence of osteoporosis is fractures.
The risk of fractures is increased with the number of risk factors.
Based on effects on mean change in lumbar spine BMD, risedronate 35 mg once a
week (n=485) was shown to be equivalent to risedronate 5 mg daily (n=480) in a oneyear, double-blind, multicentre study of postmenopausal women with osteoporosis.
The clinical programme for risedronate sodium administered once daily studied the
effect of risedronate sodium on the risk of hip and vertebral fractures and contained
early and late postmenopausal women with and without fracture. Daily doses of 2.5
mg and 5 mg were studied and all groups, including the control groups, received
calcium and vitamin D (if baseline levels were low). The absolute and relative risk of
new vertebral and hip fractures were estimated by use of a time to first event analysis.
Two placebo-controlled trials (n=3661) enrolled postmenopausal women under 85
years with vertebral fractures at baseline. Risedronate sodium 5 mg given daily for 3
years reduced the risk of new vertebral fractures relative to the control group. In
women with at least 2 or at least 1 vertebral fractures, the relative risk reduction was
49% and 41% respectively (incidence of new vertebral fractures with risedronate
sodium 18.1% and 11.3%, with placebo 29.0% and 16.3%, respectively). The effect
of treatment was seen as early as the end of the first year of treatment. Benefits were
also demonstrated in women with multiple fractures at baseline. Risedronate sodium
5 mg daily also reduced the yearly height loss compared to the control group.
Two further placebo controlled trials enrolled postmenopausal women above 70 years
with or without vertebral fractures at baseline. Women 70-79 years old were enrolled
with femoral neck BMD T-score <-3 SD (manufacturer's range, i.e. -2.5 SD using
NHANES III) and at least one additional risk factor. Women >80 years old could be
enrolled on the basis of at least one non-skeletal risk factor for hip fracture or low
bone mineral density at the femoral neck. Statistical significance of the efficacy of
risedronate sodium versus placebo is only reached when the two treatment groups
with 2.5 mg and 5 mg are pooled. The following results are only based on aposteriori analysis of subgroups defined by clinical practise and current definitions of
osteoporosis:
In the subgroup of patients with femoral neck BMD T-score <-2.5SD (NHANES III)
and at least one vertebral fracture at baseline, risedronate sodium given for 3 years
reduced the risk of hip fractures by 46% relative to the control group (incidence of
hip fractures in combined risedronate sodium 2.5 and 5 mg groups 3.8%, placebo
7.4%);

Data suggest that a more limited protection level than this may be observed in the
very elderly (>80 years). This may be due to the increasing importance of nonskeletal factors for hip fracture with increasing age.
In these trials, data analysed as a secondary endpoint indicated a decrease in the risk
of new vertebral fractures in patients with low femoral neck BMD without vertebral
fracture and in patients with low femoral neck BMD with or without vertebral
fracture.
Risedronate sodium 5 mg daily given for 3 years increased bone mineral density
(BMD) (relative to control group) in the lumbar spine, femoral neck, trochanter and
wrist and maintained bone density at the mid-shaft radius.
In a one-year follow-up study after three years of treatment with risedronate sodium 5
mg daily there was rapid reversibility of the suppressing effect of risedronate sodium
on bone turnover rate.
Bone biopsy samples from postmenopausal women treated with risedronate sodium 5
mg daily for 2 to 3 years, showed an expected moderate decrease in bone turnover.
Bone formed during risedronate sodium treatment was of normal lamellar structure
and bone mineralisation. These data together with the decreased incidence of
osteoporosis related fractures at vertebral sites in women with osteoporosis appear to
indicate no detrimental effect on bone quality.
Endoscopic findings from a number of patients (in both risedronate sodium or
placebo groups) with moderate to severe gastrointestinal complaints indicated no
evidence of treatment related gastric, duodenal or oesophageal ulcers in either group,
although duodenitis was uncommonly observed in the risedronate sodium group.

Treatment of Osteoporosis in Men
Risedronate sodium 35 mg once a week demonstrated efficacy in men with
osteoporosis (age range 36 to 84 years) in a 2 year, double-blind, placebo-controlled
study in 284 patients (risedronate sodium 35mg n = 191). All patients received
supplemental calcium and vitamin D.
Increases in BMD were observed as early as 6 months following initiation of
risedronate sodium treatment. Risedronate sodium 35 mg once a week produced mean
increases in BMD in the lumbar spine, femoral neck, trochanter and total hip
compared to placebo after 2 years of treatment. Antifracture efficacy was not
demonstrated in this study. The bone effect (BMD increase and BTM decrease) of
risedronate sodium is similar in males and females.
Paediatric population: The safety and efficacy of risedronate sodium is being
investigated in an on-going study of paediatric patients aged 4 to less than 16 years
with osteogenesis imperfecta. After completion of its one-year randomized, doubleblind, placebo controlled phase, a statistically significant increase in lumbar spine
BMD in the risedronate group versus placebo group was demonstrated; however an
increased number of at least 1 new morphometric (identified by x-ray) vertebral
fracture was found in the risedronate group compared to placebo. Overall, results do
not support the use of risedronate sodium in paediatric patients with osteogenesis
imperfecta.

5.2

Pharmacokinetic properties
Absorption: Absorption after an oral dose is relatively rapid (tmax ~ 1 hour) and is
independent of the dose over the range studied (single dose study, 2.5 to 30 mg;
multiple dose studies, 2.5 to 5 mg daily and up to 50 mg once a week). Mean oral
bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is
administered with food. Bioavailability was similar in men and women.
Distribution: The mean steady state volume of distribution is 6.3 l/kg in humans.
Plasma protein binding is about 24%.
Biotransformation: There is no evidence of systemic metabolism of risedronate
sodium.
Elimination: Approximately half of the absorbed dose is excreted in urine within the
first 24 hours, and 85% of an intravenous dose is recovered in the urine after 28 days.
Mean renal clearance is 105 ml/min and mean total clearance is 122 ml/min, with the
difference probably attributed to clearance due to adsorption to bone. The renal
clearance is not concentration dependent, and there is a linear relationship between
renal clearance and creatinine clearance. Unabsorbed risedronate sodium is
eliminated unchanged in faeces. After oral administration the concentration/time
profile shows three elimination phases with a terminal half-life of 480 hours.
Special Populations
Elderly: no dosage adjustment is necessary.
Acetyl salicylic acid/NSAID users: Among regular acetyl salicylic acid or NSAID
users (3 or more days per week) the incidence of upper gastrointestinal adverse events
in risedronate sodium treated patients was similar to that in control patients.

5.3

Preclinical safety data
In toxicological studies in rat and dog dose dependent liver toxic effects of
risedronate sodium were observed, primarily as hepatic enzyme increases with
histological changes in rat. The clinical relevance of these observations is
unknown. Testicular toxicity occurred in rat and dog at exposures considered
in excess of the human therapeutic exposure. Dose related incidences of upper
airway irritation were frequently observed in rodents. Similar effects have
been seen with other bisphosphonates. Lower respiratory tract effects were
also seen in long term studies in rodents, although the clinical significance of
these findings is unclear. In reproduction toxicity studies at exposures close to
clinical exposure ossification changes were seen in sternum and/or skull of
foetuses from rats treated with risedronate and hypocalcemia and mortality in
pregnant females allowed to deliver. There was no evidence of teratogenesis at
3.2 mg/kg/day in rat and 10mg/kg/day in rabbit, although data are only
available on a small number of rabbits. Maternal toxicity prevented testing of
higher doses. Studies on genotoxicity and carcinogenesis did not show any
particular risks for humans.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
The other components are:
Tablet core:
lactose monohydrate,
microcrystalline cellulose,
crospovidone type A,
colloidal anhydrous silica and
magnesium stearate.
Coating:
Opadry orange 20C53825,
hypromellose 6 cp (E 464),
titanium dioxide (E171),
macrogol/polyethylene glycol 400,
hydroxypropyl cellulose (E 463),
hypromellose 15 cp (E 464),
macrogol/ polyethylene glycol 800,
ferric oxide yellow (E 172),
ferric oxide red (E172) and
colloidal anhydrous silica (E 551).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Polyamide/Alu/PVC blister coated and sealed with a lacquer layer.
Blisters in packs containing 1, 2, 4, 10, 12 or 16 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited
Building 4, Chiswick Park

566 Chiswick High Road,
London, W4 5YE
U.K.

8

MARKETING AUTHORISATION NUMBER(S)
PL 14894/0675

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11/03/2010

10

DATE OF REVISION OF THE TEXT
27/12/2012

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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